1. Field of Invention
This invention includes N-pyrazole substituted 2-adenosine compounds that are useful as A2A receptor agonists. The compounds of this invention are vasodilating agents that are useful as heart imaging aids that aid in the identification of mammals, and especially humans who are suffering from coronary disorders such as poor coronary perfusion which is indicative of coronary artery disease (CAD). The compounds of this invention can also be used as therapeutics for coronary artery disease as well as any other disorders mediated by the A2A receptor.
2. Description of the Art
Pharmacological stress is frequently induced with adenosine or dipyridamole in patients with suspected CAD before imaging with T1 scintigraphy or echocardiography. Both drugs effect dilation of the coronary resistance vessels by activation of cell surface A2 receptors. Although pharmacological stress was originally introduced as a means of provoking coronary dilation in patients unable to exercise, several studies have shown that the prognostic value of 201T1 or echocardiographic imaging in patients subjected to pharmacological stress with adenosine or dipyridamole was equivalent to patients subjected to traditional exercise stress tests. However, there is a high incidence of drug-related adverse side effects during pharmacological stress imaging with these drugs, such as headache and nausea, that could be improved with new therapeutic agents.
Adenosine A2B and A3 receptors are involved in mast cell degranulation and, therefore, asthmatics are not given the non-specific adenosine agonists to induce a pharmacological stress test. Additionally, adenosine stimulation of the A1 receptor in the atrium and AV node will diminish the S-H interval which can induce AV block (N. C. Gupto et al.; J. Am Coll. Cardiol; (1992) 19: 248-257). Also, stimulation of the adenosine A1 receptor by adenosine may be responsible for nausea since the A1 receptor is found in the intestinal tract (J. Nicholls et al.; Eur. J. Pharm.(1997) 338(2) 143-150).
Animal data suggests that specific adenosine A2A subtype receptors on coronary resistance vessels mediate the coronary dilatory responses to adenosine, whereas subtype A2B receptor stimulation relaxes peripheral vessels (note: the latter lowers systemic blood pressure). As a result there is a need for pharmaceutical compositions that are A2A receptor agonists that have no pharmacological effect as a result of stimulating the A1 receptor in vivo. Furthermore, there is a need for A2A receptor agonists that have a short half-life, and that are well tolerated by patients undergoing pharmacological coronary stress evaluations.